Asenapine, whose chemical name is (3aR,12bR)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole, is a compound of formula (I):

Asenapine, disclosed in U.S. Pat. No. 4,145,434, is used in the treatment of diseases of the central nervous system, in particular schizophrenia. It has been established that asenapine is a very potent dopamine and a serotonin antagonist with antipsychotic activity.
Asenapine is marketed as maleate salt under the trade name SAPHRIS® (a registered trademark of N.V. Organon, a subsidiary of Merck & Co., Inc.).
As it is well known to those skilled in the art, the crystalline form and morphology of a solid form of a pharmaceutical compound may greatly influence its physicochemical properties, such as stability, rate of dissolution, bioavailability, and the like.
Substances are known which only appear in a single crystal form; other substances, on the other hand, can exist in two, three or even more crystal modifications. The property of some molecules and molecular complexes to assume more than one crystalline or amorphous form in the solid state is known as polymorphism, and the different forms of a compound are referred to as polymorphs. In general, polymorphism is caused by the ability of the molecule of a compound to change its conformation or to form different inter- and intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. Accordingly, polymorphs are distinct solids sharing the same molecular formula, having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family.
From a physical point of view, once salts of pharmaceutical compounds have been isolated, they can be characterized by their thermal behaviour. Thermal behavior is measured in the laboratory by such techniques as Differential Scanning calorimetry (DSC) and can be used to distinguish among polymorphs. Melting points, glass transitions, crystallinity, solvates, and/or presence of polymorphic behaviour can be evidenced by multiple endotherms, poorly defined endotherms, and endotherms near the boiling point of solvents. The potential for polymorphism may also give rise to distinct spectroscopic properties that may be detectable by X-Ray Powder Diffraction (XRPD) analysis.
The relevant polymorphism of an organo-chemical substance is always unpredictable in respect of the number of crystal modifications, the stability thereof and their behaviour in a living organism.
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, they show different physical properties of the solid state such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc. These differences in morphology and polymorphism may have drastic effects on the flowability of the milled solid (flowability affects the ease with which the material is handled during processing into a pharmaceutical product; when particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants); on development, transport stability and storage stability of individual administration forms; on the ability to produce different administration forms and on their application; on the solubility in polar or non-polar, protic or aprotic solvents, in aqueous solution, in the gastric juices or in blood serum; and finally on bio-availability. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. Other important properties of polymorphic forms relate to the ease of processing the form into pharmaceutical dosages, as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
The discovery of novel polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing a pharmaceutical dosage form, or a drug with a targeted release profile, or other desired characteristics, such as flowability and suitable rate of dissolution in aqueous fluid. Therefore, there is an ongoing research effort aimed to identifying new forms of known compounds, in the quest for ever better pharmacological properties (a lower required dosage, a faster action, . . . ).
Asenapine maleate was first obtained as anhydrous monoclinic form (also known as Form H), as described by Funke et al. in Arzneim.-Forsch/Drug Res., 40:536-539 (1999). This known form has a melting point of 141-145° C.
WO 2006/106135 discloses a new crystalline form of asenapine maleate, herein referred to as orthorhombic form or Form L, whose melting point is in the range 138-142° C.
WO 2008/040816 discloses an amorphous form of asenapine maleate, prepared via spray-drying or freeze-drying processes. However, the present inventors have found that an amorphous form prepared by means of freeze-drying is not stable, and spontaneously converts into Form H upon standing.
WO 95/23600 describes the production of a sublingual formulation of asenapine maleate. It is known that the particle size of a drug substance influences biopharmaceutical properties of the drug itself; thus, according to this document, it is desired to employ the salt in the form of powder with a small particle size, preferably about 100 μm or less. In order to reduce the particle size of the crystals, a micronization step is applied, starting from form H (monoclinic). However, some drawbacks are associated with the micronization process, since an unpredictable mixture of Form H and Form L is obtained starting with the monoclinic form. As any given form has its own physicochemical properties, a mixture of polymorphic forms of a compound gives rise to unpredictable overall properties of a formulated pharmaceutical product containing said mixture, thus affecting the effectiveness of the medicament.
On the basis of these considerations, preparation and characterization of novel solid forms of asenapine maleate is desirable.
An object of the present invention is to provide novel anhydrous and non solvate solid forms of asenapine maleate and processes for preparing them.